As reported, with the development of economic society and the aging of the population, morbidity and mortality of cardiovascular diseases have increased significantly in recent years, ranking the second place in total mortality, just behind cancer, becoming the main diseases that threaten human health. Studies showed that atherosclerosis (AS) is one of the main pathological basis of many cardiovascular diseases, making anti-atherosclerosis drugs a hot field of drug development. The study also conveyed that atherosclerosis is manifested as the yellow substances such as cholesterol and lipid in the endarterium, leading to thrombogenesis and blood supply insufficiency. Although its molecular pathology is not entirely understood, it is widely accepted that, among many factors, dyslipidemia is the most important factor in causing atherogenesis and that the formation of atheromas and arteriosclerosis are closely related to the abnormal expression of the lipid component.
Generally speaking, dyslipidemia refers to higher lipid level in plasma and higher blood viscosity caused by lipid metabolism or transfer anomaly, and blood viscosity increase which mainly characterized by an increase of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) and a decrease of high-density lipoprotein (HDL). Therefore, reduce LDL and/or increase HDL can play a role in regulating blood lipids and hence plasma lipids regulator can function as the main clinically used drug for anti-atherosclerosis.
The plasma lipids regulator commonly used in clinic are mainly statins, fibrates, bile acid binding resins, nicotinic acid and so on. Among them, the statins take effect through inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG CoA reductase), the key enzyme of cholesterol biosynthetic process, to reduce plasma LDL level, thus can reduce the morbidity of coronary heart diseases (Linsel-Nitschke P, Tall A R. Nat. Rev. Drug. Discov, 2005, 4, 193-206). However, studies also show that after using pravastatin and atorvastatin to treat patients with coronary diseases, though LDL cholesterol level can be reduced in varying degrees, these patients still have a high incidence rate of cardiovascular diseases (Cannon C P, Braunwald E, et al. N Engl J Med, 2004, 350: 1495-1504). Thus, the treatment effect of simply reducing LDL cholesterol is limited. Furthermore, some studies have shown that statins have other serious side effects such as rhabdomyolysis.
With further researches, studies have proposed many potential anti-atherosclerosis drug targets, including sphingomyelin synthase inhibitors, PPAR agonists, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein infusion, liver X receptor agonists and phospholipid transfer protein (PLTP) inhibitors. Among them, sphingomyelin (SM) and related metabolic enzymes can change lipoprotein levels while conducting a series of cell-mediated process, which suggested that they play important roles in the development of the atherogenesis.
Studies have shown that SM can induce AS in various pathways, including (1) inhibiting lipolysis of triglyceride (TG) (Park T S, Panek R L, et al. Atherosclerosis. 2006, 189(2):264-72.); (2) delay the clearance of atherogenic remnant lipoprotein (Schlitt A, Hojjati M R, et al. J Lipid Res. 2005, 46(2):196-200.); (3) affecting HDL-mediated cholesterol reverse transport, causing removal obstacles of cholesterol (Sano O, Kobayashi A, et al. J Lipid Res. 2007, 48(11):2377-84; Marmillot P, Patel S, et al. Metabolism. 2007, 56(2):251-9.); (4) ceramide and products of SM synthesis or degradation are cell regulators which can affect cell proliferation, activation and apoptosis and hence affect the atherosclerotic plaque growth and stability (Park, T.-S.; Panek, R. L.; et al. Circulation. 2004, 110, 3465-3471.); (5) LDL enriched in SM has strong cohesion and adhesion power which can make macrophages easy to aggregate on arterial wall to form foam cells thus promote atherogenesis (Fan Y, Shi S, et al. Arterioscler Thromb Vasc Biol, 2010, 30:2114-20.).
Epidemiological surveys also show that: there is an independent correlation between human SM level and AS, and that the plasma concentration of SM is an independent risk factor to AS, thus it is of indicative meaning in evaluating AS development (Jiang, X.-C.; Paultre, F.; et al. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 2614-2618; Zhiqiang Li; Maria J. Basterr; et al. Biochimica et Biophysica Acta. 2005, 1735, 130-134.); animal studies have shown that inhibiting de novo biosynthesis of SM can efficiently reduce plasma cholesterol and triglyceride levels and increase the HDL-cholesterol, thereby preventing further lesion of AS (Park, T.-S.; Panek, R. L.; et al. Circulation. 2004, 110, 3465-3471.); therefore, decrease of plasma SM or inhibition of SM synthesis are believed to retard or even block athegogenesis.
Studies also show that sphingomyelin synthase (SMS) is the key enzyme of the last step of SM de novo biosynthesis, which can catalyze ceramide and phosphatidylcholine (PC) to synthesis SM. Further studies find that SMS can directly regulate SM level, and that SMS overexpression is a common phenomenon in atherosclerotic pathological-changed tissue, making it to be one of the key indicators of atherosclerosis (Xian-cheng Jiang; Furcy Paultre; et al. Arterioscler. Thromb. Vasc Biol. 2000, 20, 2614-2618 Zhiqiang Li; Tiruneh K. et al. Biochimica et Biophysica Acta, 2007, 1771, 1186-1194.). In the animal experiments, atherosclerotic plaques in arcus aortae of SMS2 and apoE double-gene knockout mice are dramatically reduced, SM and other lipids in brachiocephalic artery are obviously decreased, while does not influence their normal physiology function (Fan Y, Shi S, et al. Arterioscler. Thromb. Vasc Biol, 2010, 30:2114-20.), which insinuates that the SMS catalytic synthesis of SM is at the last step of SM biosynthesis cycle and may cause relatively slighter potential adverse effects when inhibited. With all the evidence above, it is believed that reduce SM level through inhibiting SMS is a new method to treat atherosclerosis. SMS has potential advantages as an anti-atherosclerosis target. Thus SMS inhibitors can make a novel medication for AS.
Furthermore, some studies have found that SMS2 deficiency can prevent obesity and insulin resistance caused by high-fat diets; meanwhile, it is difficult to observe significant mature fatty plaques in the livers of SMS2 knock-out mice, suggesting that SMS2 can take part in formation of liver fatty plaques and can induce obesity and type II diabetes (Susumu Mitsutake, Kota Zama, et al. Journal of Biological Chemistry. 2011, 286(32), 28544-28555). Plasma SM decrease caused by SMS2 deficiency can improve animal tissue and physical insulin sensibility (Li Z, Zhang H, et al. Mol. Cell. Biol. 2011, 31(20): 4205-4218). Therefore, SMS small-molecule inhibitors can prevent and treat obesity, fatty liver, type II diabetes, and other metabolic syndromes.
D609 is one of the reported SMS inhibitors (Aimin Meng; Chiara Luberto; et al. Experimental Cell Research, 2004, 292, 385-392.), having a weak inhibitory activity of IC50=375 μM along with an highly unstable xanthate structure (Bai, A. et al. J. Pharmacol. Exp. Ther. 2004, 309, 1051-1059), thus has a short half-life time; It is reported that with the method of homology modeling, a hSMS1 3D-protein structure model was firstly built (Zhang Ya; Lin Fu; et al. Chin. J. Chem. 2011, 29, 2421-2429), with which the substrate binding site of SMS was determined and varified through biological experiments (Calvin Yeang; Shweta Varshney; et al. Biochimica et Biophysica Acta, 2008, 1781, 610-617.). Furthermore, based on this 3D-protein model and the varified enzyme-substrate binding site, a new compound D2 was found as an SMS inhibitor (Xiaodong Deng, Fu Lin, et al. European Journal of Medicinal Chemistry, 2014, 73, 1-7). Compared with D609, D2 has a higher SMS2 inhibitory activity, with IC50=13.5 μM in in vitro trials. However, it still has some drawbacks: the activity which is not good enough; the existence of potential toxic cyano group; and poor physical and chemical properties such as solvability and stability.